Biomarkers of Neurobiologic Recovery in Adults With Sport-Related Concussion

Key Points Question Do distinct trajectory subgroups exist in the serum levels of glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) following sport-related concussion? Findings In this cohort study of 81 individuals with sport-related concussion, in a subset of cases, increases in GFAP and NfL levels were substantial and persisted for at least 4 weeks. Individuals in these extreme biomarker subgroups were more likely to have experienced loss of consciousness (LOC) and longer to return to training times. Meaning The findings of this study suggest the utility of serial measurements of GFAP and NfL to track neurobiologic recovery, with the association between LOC and extended biomarker elevations supporting the use of LOC for informing more conservative return-to-play timelines.

Cognitive assessments performed with the Cogstate found no differences in the Detection (C), Identification (D), One Card Learning (E) or the One Back task (F) between sport-related concussion participants with and without loss of consciousness (LOC).sLOC -: No self-reported loss of consciousness.sLOC + : Self-reported loss of consciousness.
eTable 1: Sample size, median and interquartile range for sport-related concussion, musculoskeletal injury and healthy control groups at each time-point.

eFigure 1 :
Representative flow chart of participant recruitment, time-point attrition, and exclusion from primary group analyses.SRC: Sport-Related Concussion.GFAP: Glial Fibrillary Acidic Protein.NfL: Neurofilament light.LOC: Loss of Consciousness.Created with BioRender.comeFigure 2: The profiles of GFAP and NfL in musculoskeletal injury and healthy control participants.No differences were found in the profiles of GFAP (A) or NfL (B) in musculoskeletal injury or healthy control participants.Statistical comparisons are made between the MSK and healthy control groups only.GFAP: Glial Fibrillary Acidic Protein.NfL: Neurofilament light.MSK: Musculoskeletal.HC: Healthy Control.SRC: Sport-related concussion.eFigure 3: The profile of RPQ symptom severity score in sport-related concussion and control participants.Symptom evaluations performed with the symptom severity score of the Rivermead Post Concussion Questionnaire revealed a greater severity of symptoms in the sport-related concussion (SRC) participants compared to control participants at 24hrs (p<0.0001),1w (p<0.0001) and 2w (p=0.0009).*** and **** denotes p<0.001 and p<0.0001 respectively.SRC: Sport-related concussion.eFigure 4: Cognitive performance over time in sport-related concussion and control participants.Cognitive assessments performed with the Cogstate found an increased speed in the SRC participants compared to control participants in the Detection (A; p=0.036) and Identification task (B; p=0.022).While no differences were found in the One Card Learning (C), decreased speed in the One Back task was found at 24h (D; p=0.0009) and 1w (p=0.03),* and ***denotes p<0.05 and 0.001 respectively.eFigure 5: Cognitive profiles of sport-related concussion participants grouped by GFAP and NfL subgroup.Cognitive assessment with the Cogstate revealed no differences in sport-related concussion (SRC) in GFAP or NfL subgroups compared to control participants for the Detection (A, B), Identification (C, D), One Card Learning (E, F) or One Back task (G, H).Data is presented as min-max box plots.GFAP: Glial fibrillary acidic protein.NfL: Neurofilament light.

eFigure 6 :
Cognitive profile for sport-related concussion participants with and without a loss of consciousness.

Model fit statistics for growth mixture modeling to determine the number of GFAP subgroups.
n: number.IQR: Interquartile range.h:hours.d:days © O'Brien WT et al.JAMA Network Open.eTable 2:

eTable (continued) Model fit statistics for growth mixture modelling to determine the number of GFAP subgroups.
The chosen model is bolded.AIC: Akaike Information Criterion.BIC: Bayesian Information Criterion.©2024 O'Brien WT et al.JAMA Network Open.eTable 3

Model fit statistics for growth mixture modeling to determine the number of NfL subgroups.
© 2024 O'Brien WT et al.JAMA Network Open.eTable 3 (continued):

Model fit statistics for growth mixture modelling to determine the number of NfL subgroups.
The chosen model is bolded.AIC: Akaike Information Criterion.BIC: Bayesian Information Criterion.eTable 4:

Group Assignments for individuals who participated twice.
© 2024 O'Brien WT et al.JAMA Network Open.eTable 5:

Post hoc results for comparisons of serum NfL over time in the musculoskeletal injury group compared to healthy control group.
Values are relative to the healthy control group.MD: Mean difference.GFAP: Glial fibrillary acidic protein.NfL: Neurofilament light.

Post-hoc results for longitudinal outcomes in sport-related concussion (SRC) participants grouped by GFAP subgroup.
© 2024 O'Brien WT et al.JAMA Network Open.eTable 7 (

eTable 11: Linear Mixed Model results for 24hr GFAP, 1w NfL and LOC as predictors of 24hr RPQ Symptom Severity and Time to Return to Training.
Return to training affected by end-of-season, COVID-19 lockdowns, or failure to return to training meant 15 cases were not included.*denotes values are adjusted for age and BMI.IRR: Incident Rate Ratio.